The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

Skerratt, Sarah E. and Andrews, Mark and Bagal, Sharan K. and Bilsland, James and Brown, David and Bungay, Peter J. and Cole, Susan and Gibson, Karl R and Jones, Russell and Morao, Inaki and Nedderman, Angus and Omoto, Kiyoyuki and Robinson, Colin and Ryckmans, Thomas and Skinner, Kimberly and Stupple, Paul and Waldron, Gareth (2016) The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain. Journal of Medicinal Chemistry, 59 (22). pp. 10084-10099. ISSN 0022-2623. (doi:https://doi.org/10.1021/acs.jmedchem.6b00850) (Full text available)

Abstract

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially “druggable” point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.

Item Type: Article
Subjects: Q Science > QD Chemistry > QD431 Organic Chemistry- Biochemistry- Proteins, peptides, amino acids
R Medicine
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: David Brown
Date Deposited: 02 Dec 2016 11:19 UTC
Last Modified: 31 Jan 2017 12:24 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/59375 (The current URI for this page, for reference purposes)
Brown, David: https://orcid.org/0000-0003-4605-4779
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